PT  - JOURNAL ARTICLE
AU  - Hung, Chien-Min
AU  - Lombardo, Portia S.
AU  - Malik, Nazma
AU  - Brun, Sonja N.
AU  - Hellberg, Kristina
AU  - Van Nostrand, Jeanine L.
AU  - Garcia, Daniel
AU  - Baumgart, Joshua
AU  - Diffenderfer, Ken
AU  - Asara, John M.
AU  - Shaw, Reuben J.
TI  - AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy
AID  - 10.1126/sciadv.abg4544
DP  - 2021 Apr 01
TA  - Science Advances
PG  - eabg4544
VI  - 7
IP  - 15
4099  - http://advances.sciencemag.org/content/7/15/eabg4544.short
4100  - http://advances.sciencemag.org/content/7/15/eabg4544.full
SO  - Sci Adv2021 Apr 01; 7
AB  - The serine/threonine kinase ULK1 mediates autophagy initiation in response to various cellular stresses, and genetic deletion of ULK1 leads to accumulation of damaged mitochondria. Here we identify Parkin, the core ubiquitin ligase in mitophagy, and PARK2 gene product mutated in familial Parkinson’s disease, as a ULK1 substrate. Recent studies uncovered a nine residue (“ACT”) domain important for Parkin activation, and we demonstrate that AMPK-dependent ULK1 rapidly phosphorylates conserved serine108 in the ACT domain in response to mitochondrial stress. Phosphorylation of Parkin Ser108 occurs maximally within five minutes of mitochondrial damage, unlike activation of PINK1 and TBK1, which is observed thirty to sixty minutes later. Mutation of the ULK1 phosphorylation sites in Parkin, genetic AMPK or ULK1 depletion, or pharmacologic ULK1 inhibition, all lead to delays in Parkin activation and defects in assays of Parkin function and downstream mitophagy events. These findings reveal an unexpected first step in the mitophagy cascade.